The overall purpose of this study is to explore the mechanisms by which the cerebrovascular system adapts to long-term hypoxemia. Our overall hypothesis is that the changes in cerebrovascular reactivity in high- altitude acclimatized fetuses and adults are secondary to alterations in the basic cellular and biochemical mechanisms which regulate vascular function. Specifically, we shall test three hypotheses as follows: I. The catecholamine hypothesis proposes that changes in cerebrovascular catecholamine metabolism (norepinephrine and/or reuptake) are associated with the vascular reactivity changes in response to long-term hypoxemia. II. The alpha receptor hypothesis suggests that alterations in cerebrovascular alpha receptor types (alpha 1 and/or alpha 2), number, or receptor gain (i.e., the magnitude of the second messenger inositol triphosphate response) account for the reactivity changes. III. The structural protein hypothesis suggests that changes int he cerebrovascular structural proteins collagen and/or elastin account for these changes. Each of these hypotheses will be examined in three experimental groups: term fetus, pregnant adult, and nonpregnant adult. Each of these groups will include two subgroups: normoxic controls and high altitude acclimatized animals. Thus, there will be a total of six experimental groups in which cerebrovascular changes will be studied to test each hypothesis. To the common carotid, basilar, posterior communicating, and middle cerebral arteries, we will measure 1) concentrations of catecholamines and their metabolites, 2) norepinephrine uptake, 3) alpha 1 and alpha 2 receptor direct binding, 4) receptor binding by quantitative autoradiography, 5) receptor dose-response relations, 6) receptor gain, inositol triphosphate (IP3) concentrations, 7) vascular reactivity, 8) elastin and collagen concentrations. Taken as a whole, the studies have potential for new and important insights into the basic mechanisms of the brain's defenses to hypoxia, e.g., specific receptor function, signal transduction, and vascular smooth muscle function. The proposed studies will lead to greater insights into the regulation of cerebral vascular reactivity per se, and the pathophysiology of clinical problems associated with the dysregulation of cerebral blood flow, intracerebral hemorrhage, various neurological sequelae (such as cerebral palsy, seizure disorders, and mental retardation, minimal brain dysfunction, et cetera), as well as for a deeper understanding of the adaptations which serve to maintain fetal oxygen availability under such a stress. In addition, they will provide a deeper understanding of the physiologic basis of hypoxic-induced acclimatization responses in general, and the basis of the vascular responses during the course of development and in women during pregnancy.